This review focuses primarily on the mammalian medium and long-chain fatty acid coenzyme A ligases that have been implicated in the metabolism of xenobiotic carboxylic acids such as pesticides, arylpropionate non steroidal anti-inflammatory drugs and the hypolipidaemic clofibrate and its congeners. Evidence of multiplicity of mitochondrial and microsomal enzymes and their respective substrate/inhibitor profiles are discussed. For completeness, where appropriate, details of non-substrate inhibitors have also been included. Although knowledge is limited at present with respect to the medium-chain enzymes, aspects of regulation particularly the in vivo, in vitro role of peroxisome proliferators and current knowledge of the molecular biology of the long-chain fatty acid CoA ligase superfamily are documented. Additionally, alignment of thirteen cloned mammalian fatty acid CoA ligases using criteria established for the CYP and UGT superfamilies has enabled construction of a phylogenetic tree that clearly defines three families. Catalytic data are still limited and the xenobiotic substrate/inhibitor profiles of the recombinant proteins are incomplete. Finally, with increasing recognition of the importance of fatty acyl-CoA esters as physiological regulators of cell function including gene expression, the review concludes with a discussion of the metabolic fate and toxicity of xenobiotic acyl-CoA esters.